Many enantiomerically pure cycloalkanones substituted at the 3-position with hydrocarbon groups are useful as both synthetic intermediates and as physiologically active natural products. For example, the plant stress metabolite solavetivone methylenomycin is an (R)-3-methylcyclohexanone and the anti-tumor eudesmanolide pinnatifidin is an (S)-3-methylcyclohexanone. Posner et al., Tetrahedron Lett., 25(4), 379 (1984). Traditionally, these compounds have been formed by the stoichiometric addition of hydrocarbon groups to cycloalkanones.
Another application of the stoichiometric addition of hydrocarbon groups to cycloalkanones has been in the production of prostaglandins. The prostaglandin family is known to control a wide variety of physiological responses in human and animal tissues. In particular, the prostaglandins are known to be involved in the regulation of systems including the circulatory system, the respiratory system and the digestive system.
Prostaglandins derived from synthetic processes have been employed in a variety of pharmaceuticals. For example, the prostaglandin 15-deoxy-16-hydroxy-16-methyl-PGE methyl ester has been shown to be a potent anti-ulcer drug. The formula for this particular prostaglandin is as follows: ##STR1##
In the synthesis of prostaglandins, a stoichiometric conjugate addition reaction of an organocopper reagent to cyclopentenone has been employed as a key step. This addition proceeds as follows: ##STR2##
The stoichiometric synthesis of prostaglandins is more fully described by R. Noyori et al., in Angew. Chem. Int. Ed. Engl. 23, 847-876 (1984).
Stoichiometric reactions of the type described above may produce products having high enantiomeric excesses; however, they still require one equivalent of reagent per one equivalent of optically active product. Previous workers have attempted to develop catalytic enantioselective systems for other types of reactions with mixed results. Most notably, catalytic asymmetric hydrogenation of unsaturated compounds has been demonstrated by Bosnich and co-workers using rhodium-phosphine catalysts (Fryduk, M. P. and Bosnich, B., J. Amer. Chem. Soc. 100:5491 (1978). Sharpless and co-workers have discovered the asymmetric epoxidation of allylic alcohols by alkyl hydroperoxides with excellent enantiomeric excess (e.e.) utilizing titanium-tartrate catalysts. (Katsuki, T. and Sharpless, K. B., U.S. Pat. No. 4,471,130.) Brunner et al. have attempted a catalytic enantioselective hydrosilylation of acetophemone using a rhodium complex of N,N-di(s,s,-phenethyl) aminotroponeimino with poor results (Brunner, H. et al., T. Organomet. Chem. 295:211-221 (1985)).
A reagent system which successfully provides for the catalytic production of optically active .beta.-substituted alkanones would be of great utility. Thus, a need exists for reagents and methods which catalytically enhance the production of beta-substituted cycloalkanones of high enantiomeric purity.